The CCR5 gene encodes a molecule which serves as a secondary receptor on macrophages and CD4+ T cells for certain strains of HIV-1. We and others have previously identified a mutant of CCR5 characterized by a 32 base pair deletion, which protects from infection in homozygotes and prolongs time to AIDS in infected heterozygotes. We have continued to type cohorts for this mutation with a total number of 672 HIV- and 1,935 HIV+ individuals. While the genotype frequencies of homozygous wild- type, as well as the heterozygous wild-type/deletion, is equivalent in the HIV-1- and HIV-1+ samples, homozygotes for CCR5delta32 are significantly more frequent in HIV-1- than HIV-1+ individuals (p=0.00000000007). We have also identified 16 additional variants in the coding region of the CCR5 gene, all 3 of which are codon coding altering. The high predominance of codon- altering alleles among CCR5 mutants is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures. We have identified two HIV-1+ individuals who are homozygous for the CCR5delta32 mutation, providing evidence that although homozygosity for this mutation provides strong resistance to HIV-1 infection, it does not afford complete protection. Preliminary analysis has suggested that these individuals became infected with HIV-1 isolates which use the CXCR4 molecule, rather than CCR5, as a coreceptor for infection. A genotype survey of 4,008 individuals revealed a cline in the CCR5delta32 frequencies from north to south in Europe. The variant was missing in native Africans, native Americans, and East Asian ethnic groups. The data indicate that the mutation occurred once in an ancestral Caucasian population.